Research Article - Journal of Drug and Alcohol Research ( 2021) Volume 10, Issue 10
Gastro Retentive Microspheres-Drugs for Parkinsons diseaseR.Prasanthi1, B.Haarika1 and S.Selvamuthukumar2
2Department of Pharmacy, Annamalai University, India
Received: 01-Sep-2021;Accepted Date: Sep 15, 2021; Published: 22-Sep-2021
Microspheres are small micron size particles ranging from 1 micron to 1000 microns and are free-flowing particles. These are prepared to acquire prolonged and controlled drug delivery to enhance the bioavailability, stability, and target-specific sites. These are made up of natural or synthetic polymers and these are of various types. In this review majorly three types of microspheres are discussed namely mucoadhesive or buccoadhesive microspheres, magnetic microspheres, and floating microspheres. General methods of preparation techniques like single emulsion, double emulsion, polymerization, solvent extraction, phase separation or coacervation, spray dryings or pray concealing, orifice ionic gelation method. Microspheres evaluation methods include flow properties, Swelling index, isoelectric point, in vitro dissolution test, ATR FTIR. Advantages, disadvantages, and their applications are discussed in detail. A note on Parkinsonism is added to the review. The scope to develop microspheres of MAO-B inhibitors and other agents in the treatment of Parkinson’s disease is discussed.
Controlled release; Mucoadhessive; Floating; Microspheres; MAO-B inhibitors; Parkinson’s disease
A drug is defined as the active pharmaceutical ingredient that upon formulation into dosage form using excipients is used to deliver drugs into the body to exhibit a therapeutic effect. Drug administration to show the therapeutic effect in the body is known as drug delivery. Various conventional dosage forms are developed that can be classified as oral, buccal, nasal, rectal, sublingual, intramuscular, intravenous, and subcutaneous based on their mode of administration into the body. Each has its advantages and disadvantages. A multidisciplinary approach including polymer science, pharmaceutics, bio-conjugation, and molecular biology to deliver and target the drug in a specific tissue is gaining enormous significance. Many new technologies are under development to overcome issues faced using conventional dosage forms like drug degradation, harmful side effects, bioavailability problems, and problems related to the delivery of the drug to the target site .
By using novel-advanced technologies and new dosage forms, a Novel drug delivery system (NDDS) has been developed. These are acquiring more importance as the potency of the drug is enhanced and the action of the drug is specific and localized. Major advantages of NDDS are, when the conventional dosage forms are administered the concentration of the drug content levels in the body fluctuates and are not maintained in the therapeutic ranges whereas the novel drug delivery systems once administered, it maintains drug level within the effective therapeutic ranges and utilizes the maximum drug-induced into the body, preventing fluctuations and toxicity. Novel drug delivery systems can release the drug in a controlled manner for a specified period and in specific locations, for expensive drugs, these formulations can make the best use of the drug and decrease the production cost .
NDDS are classified into different modes based on their technologies used as follows .
Targeted drug delivery system
These systems target the specific site in the body and release the drug in a controlled manner for a period so that drug fluctuations are minimized. These systems are exclusively suitable for cancerous tissues in the body that can target the specific tumor tissue and release the drug at the targeted area. The drug becomes active only at the targeted site; hence, the tissues in the other body parts are not affected by the drug, this minimizes side effects and toxicity.
Controlled drug delivery system
These dosage forms are modified in such a way that the drug is released over a long time, maintaining the drug in the effective therapeutic region for prolonged periods. The dosage forms are modified in such a way that the release of the drug can be sustained and maintained for a specific period for slow and controlled release. They can be modified into delayed-release forms from which the drug is released after a lag time and show its action.
Modulated drug delivery system
These are novel drug delivery systems utilizing devices for drug delivery for example inhalers, nebulizers etc. NDDS based on drug delivery systems is classified as
Carrier-based drug delivery system
Drug is loaded onto carriers and delivered into the body. Various carriers include nanoparticles, Niosomes, Liposomes, Microspheres, Monoclonal antibodies, and Resealed erythrocytes.
Transdermal drug delivery system (TDDS)
These are an integral part of NDDS which are applied on intact skin and are self-sustained, discrete dosage forms that deliver the drug to the systemic circulation through the skin. Various types of TDDS include Sonophorosis, and Osmotic pump drug delivery, and Micro-encapsulation.
This review is focused on one of the novel drug delivery carrier microspheres, its advantages and disadvantages, preparation methods, characterization, and recent advances. Microspheres are freely flowing powders that are small size spherical particles of micron size, ranging from 1 micron to 1000 microns, and are prepared for sustained release formulations. These are biodegradable and are prepared from polymeric or protein matrix and NA these dosage forms have 200 micron size microspheres. These NA is solid or dispersed in the embedded protein or polymeric matrix and releases the drug is aimed to be in a controlled fashion [4,5].
Materials Used For the Preparation of Microspheres
Materials used in the preparation of microspheres are natural and synthetic polymers. Synthetic polymers are used for bio-degradable and non-biodegradable polymers [6–8]. Few examples under polymers are as follows:
These are obtained from natural sources of carbohydrates such as chitosan, starch, agarose, carrageenan, sources of proteins such as collagen, gelatine, and albumin, and sources of chemically modified carbohydrates such as poly starch and poly dextran [9,10].
Synthetic non-biodegradable polymers
Acrolein, epoxy polymers, polymethyl methacrylate, glycidyl methacrylate .
Synthetic biodegradable polymers
Glycosides and lactides and their copolymers, poly anhydrides, poly alkyl cyanoacrylates .
Types of Microspheres
The three major types of Gastro-retentive microspheres are
Bioadhesive or Mucoadhesive microspheres
In these mucoadhesive polymers like cellulose derivatives, pectin, chitosan, alginate, hyaluronic acids exhibiting adhesive properties are used in preparation. Hence, the microspheres exhibit adhesion properties, when coming in contact with the mucous layer, they get adhere to the mucosal linings in the oral, nasal, ocular, rectal and vaginal mucosa. Thus offering localized drug delivery with enhanced absorption and increases bioavailability due to increased intimate contact with the mucosa, hence having a high surface to volume ratio [13–18].
Magnetic carriers like chitosan; dextran is incorporated into the formulation of microspheres. The drug can be encapsulated or conjugated onto these microspheres; the magnetic carriers can be localized in the targeted region using a powerful magnetic field outside the body and deliver the drug at the targeted site. This will localize the maximum amount of the drug was injected into the body at the site of action, thus less dose of the drug can be injected to show maximum therapeutic effect [19-23].
In this technique, the drug-loaded microspheres float on the gastric fluid and remain buoyant for a prolonged period by slowly releasing the drug. These formulations have less bulk density than the gastric fluid hence they float. The microspheres may be the effervescent type that contains swellable polymers like chitosan incorporated with effervescence releasing compounds like sodium bicarbonate and citric acid and thereby upon contact with the gastric fluid releases carbon dioxide, become less dense and float. Non-effervescent floating microspheres have highly swellable hydrocolloids mixed with polymers which swell rapidly when comes in contact with the gastric fluid and become less dense and hence float [23–26].
General Methods of Preparation of Microspheres
• Single emulsion method
• Double emulsion method
• Solvent extraction
• Phase separation/coacervation
• Spray drying and spray concealing
• The orifice ionic gelation technique
Single emulsion technique
Natural polymers are dissolved or dispersed in an aqueous solution and the dispersed droplets are then mixed with a non-aqueous medium. The obtained emulsion is then crosslinked using chemical cross linkers such as glutaraldehyde, formaldehyde, or subjected to heating. Then, this is subjected to centrifugation for isolation of the microspheres. The microspheres thus obtained after centrifugation are subjected to washing and followed by filtration .
Double emulsion technique
In this method, initial water in oil (w/o) emulsion is prepared and then this prepared emulsion is dispersed in water continuous phase to get w/o/w emulsion which is suited for water-soluble drugs? The aqueous polymer protein solution is dispersed in the chosen lipophilic organic continuous phase. This is subjected to homogenization for emulsion formation. To this primary emulsion, an aqueous solution of Polyvinyl Alcohol (PVA) is added from that w/o/w multiple emulsion is formed. This mixture is subjected to solvent extraction or solvent evaporation, then filtered to obtain microspheres. These prepared microspheres are subjected to washing using an organic solvent to remove traces amounts of oil. The active ingredient can be added to the aqueous protein solution that is encapsulated by the lipophilic continuous phase [28,29].
In this method, the Active Pharmaceutical Ingredient (API) is mixed with an aqueous solution of sodium hydroxide using a surfactant. The above mixture is subjected to heating, which results in polymerization. After polymerization, the mixture is kept aside for settling from this mixture microsphere is obtained .
Phase separation/Coacervation technique
In this method, the first polymer solution is prepared, so that the drug is added to make it an aqueous solution. Then, to this aqueous solution, phase separation is induced by the addition of co-solvents, salts, or changes the pH of the solution, or adding incompatible polymer. This results in the formation of polymer-rich globules that on hardening the process to obtain microspheres .
Spray drying/Spray congealing
In this method, the volatile polymer solution is prepared using organic solvents like acetone. The drug is dissolved in the polymer solution and subjected to high-speed homogenization for uniform mixing. This solution is then subjected to spray drying in which the drug solution is sprayed like a stream into hot air results in atomization. From a fine mist of spray, the solvent gets evaporated simultaneously leaving the dry particles in the air; the dry particles thus obtained are small spherical microspheres .
Solvent extraction technique
In this method, the organic solvent is extracted using a water solution, hence water-soluble organic solvents like Isopropyl Alcohol (IPA) are used for the preparation of the polymer solution. Then, the organic phase is removed by extraction of the organic solvent. As the organic solvent used in this method is water-soluble, water is used for organic phase extraction and the microspheres thus obtained are filtered and washed. In this method, the hardening time in the formation of microspheres is reduced .
The orifice ionic gelation technique
In this method, a homogenous polymer solution is prepared by dissolving a mixture of sodium alginate and Mucoadhesive polymers like pectin, chitosan into the purified water. To this solution, the active ingredient is added and stirred continuously until a viscous dispersion is obtained. A 10% calcium chloride solution is prepared and to this solution, the viscous solution of the drug dispersion is added manually dropwise using 18 size syringe needle gauge. The added droplets are left in the calcium chloride solution for 20 mins to complete the curing process and thereby producing spherical and rigid microspheres. Then, is solution is filtered to obtain microspheres and dried at 45°C for 12 hours [33,34].
Loading of drug
The Active Pharmaceutical Ingredient (API) is loaded onto microspheres by physical entrapment, chemical linkage and surface adsorption in two ways
1. During the preparation of microspheres
2. After the formation of the microspheres.
Evaluation of Microspheres
The percentage yield of microspheres
The obtained microspheres are dried thoroughly and accurately weighed and calculated as follows %Yield=(mass of microsphere obtained/total weight of drug and polymer) ×100
Particle size analysis
Particle size analysis is done using the sieving method, particle size distribution; particle size determination is simultaneously calculated and represented graphically. Based on particle size, the drug release rate can be determined.
Angle of repose
This is done by a conventional fixed funnel method . The free-flowing powder is poured from the funnel onto the paper; the funnel is adjusted in such a way that the heap of the poured powder touches the funnel tip. The area of the powder that is fallen on the paper is circled and its diameter is noted and the angle of repose is calculated as follows
The angle of repose (θ)=Tan -1 h/r
θ=angle of repose in degrees
h=height of the pile
r=radius of the base
Carr’s compressibility index
It is the measurement of flow property and is obtained from the bulk volume and tapped volume.
Carr’s compressibility index=(Vb-Vt)/Vb× 100
Determination of the drug content, entrapment efficiency
The required amount of the prepared microspheres is weighed accurately and crushed into powder using a mortar and pestle. This is dissolved in 100 ml of water and kept aside for 12 hours. The next day supernatant is collected and filtered and analysed for drug content using a UV spectrophotometer. The drug content and entrapment efficiency can be calculated as the ratio of the actual drug content to the theoretical drug content .
Percentage entrapment efficiency=(Actual Drug Content / Theoretical Drug Content) × 100
Accurately weighed amount equivalent to 50 mg of the drug (microspheres) is added to different solvents (100 ml) like distilled water and buffer solutions of pH 1.2, 4.5, and 7.4, kept in an orbital shaker which is maintained at 37°C and shaken occasionally. The weight of swollen microspheres was noted. This is done until equilibrium is attained and no more swelling is seen thereafter. The Swelling Index (SI) is calculated as follows.
We = Initial weight of microspheres
Wo = Weight of microspheres at equilibrium swelling in the media
The isoelectric point can be determined using a micro-electrophoresis apparatus in which electrophoretic mobility of microspheres can be determined. The mean velocity of particles at different pH values ranging from 3-10 is calculated by measuring the time of particle movement over a distance of 1 mm. The electric mobility of the particle can be determined using the above-obtained data .
In vitro dissolution testing
In this method, dissolution apparatus USP XXIII is used with the basket at 37°C ± 0.5°C with varying volumes of dissolution media as required from 100 ml–500 ml of varying speed of 50 rpm-100 rpm is set. A sample equivalent to 100 mg microspheres is loaded into the dissolution apparatus and aliquots of samples were periodically withdrawn at regular time intervals and replace with fresh dissolution media is added to maintain sink conditions. The samples collected were analysed at an appropriate wavelength using a UV spectrophotometer .
Attenuated total reflectance-Fourier transforms infrared spectroscopy (ATR-FTIR)
The ATR-FTIR provides information on the surface composition of the microspheres. It is used for the determination of the degradation of the polymeric matrix of the carrier system and the surface of the microspheres is investigated by measuring ATR .
• Controlled, sustained, and targeted release from the formulation.
• Avoid gastric irritation and the first-pass effect.
• Increased bioavailability because of the small size.
• Dosing frequency or reduction in overall dose in a day.
• Enhanced flow properties and dispersibility.
• Enhanced drug solubility
• Protection of unstable and sensitive drugs.
• Anticancer drugs to the tumour site can be targeted.
• Enhancement of shelf-life by preventing degradative reactions.
• Improved patient compliance.
• A common problem with the controlled release dosage form is dose dumping. This is the main disadvantage as the drug quantity in the formulation is high for controlled release, once if the formulation loses its integrity there is a high dose release in the body at once, which leads to toxicity.
• These dosage forms have a caution that cannot be crushed or broke or chewed as these are modified release dosage forms.
• Sometimes at the injection site embolism can be seen leading to potential toxicity
• The reproducibility is less during the formulation process the production costs is also high.
Oral drug delivery
The film-forming nature of the polymers and the pH sensitivity coupled with the reactivity of primary amine groups make microspheres very unique for the formulation of a novel approach for enhanced bioavailability of the drug through oral delivery.
As the microsphere formulation has polymers with bioadhesive properties, the formulation when comes in contact with the mucosal linings gets swell easily, increasing the residence time in the nasal mucosa that enhancing the bioavailability of the drug.
The polymer’s mucoadhesive property acts as an excellent absorption enhancer in the buccal cavity.
Gastrointestinal drug delivery
The polymers like Eudragits having internal cavities used in the preparation of microspheres exhibit floating proper ties and remain buoyant when coming in contact with the GI fluids and release the drug in a controlled fashion.
Blood flow determination
Here fluorescent microspheres were prepared using polystyrene, polyvinyl toluene. The fluorescent dye enters the swollen microspheres and enters the pores of microspheres. Upon swelling of these microspheres entrap the fluorescent dye and when injected locally get lodged in the capillaries. The fluorescent dye is extracted from the tissue sample is quantified using a spectrofluorometer.
Microspheres in chemotherapy
Microspheres act as carriers in many anticancer treatments, passive targeting through Enhanced Permeability and Retention (EPR) effect and active targeting through ligand coupling receptor .
disorder in which dopaminergic neurons in the substantia nigra slowly degenerate. Hence, the decrease in dopamine levels occurs, which leads to Parkinson’s disease. Motor and non-motor functions both are affected by Parkinson’s disease. The support of treatment is Levodopa (LD) but in later stages, stress-induced dyskinesia is seen as a side effect. Hence alternative treatments with other drugs are prescribed along with LD. Symptoms of Parkinsonism include involuntary movements, bradykinesia, impaired balance, coordination, tremors, and rigidity. Non-motor symptoms include mood disorders, cognitive impairment, sleep alterations, and hallucinations. Parkinsonism is most commonly seen in people above 60 years of age, and in few members below 20 years of age which is called juvenile Parkinsonism. The chances of occurrence of PD are more in males than females . Causes of Parkinson’s disease are age factors, genetic, environmental factors, and sometimes head injuries. Patients whose family members have a history of PD or persons when exposed to chemical toxins such as carbon monoxide, organic solvents such as manganese, and certain pesticides are most likely to have Parkinsonism .
In the treatment of PD many medications are available and in severe conditions, sometimes surgery is advised. Medication includes carbidopa-levodopa antagonists, monoamine oxidase–B inhibitors (MAO-B inhibitors), Catechol-O-methyl Transferase (COMT) inhibitors, anticholinergic drugs, and amantadine. This review focused on MAO-B inhibitors, which inhibit the breakdown of dopamine in the brain. MAO-B is an enzyme in the brain responsible for dopamine breakdown, thus by inhibiting this enzyme action dopamine in the brain is not metabolized. Examples of MAO-B inhibitors are Selegiline and Rasagiline .
Tables 1,2 and 3 gives the information regarding microsphere formulations approved, under approval and approval formulation with polymer and their category [44–48].
|Risperidone||RISPERDOL, CONSTA||Double Emulsion (Oil In Water)|
|Naltrexone||VIVITROL, LUPRON DEPOT||Double Emulsion (Oil In Water)|
|Octreotide||SANDOSTAIN LAR||Phase Separation|
|Somatropin||NUTROPIN||Cryogenic Spray Drying|
|Triptorelin||TRELSTAR DEPOT||Phase Separation|
|Buserelin||SUPRECUR MP||Dispersion method|
|Lanreotide||SOMATULINE LA||Phase Separation|
|Bromocriptine||PARLODEL LAR||Spray Drying|
Table 1: List of microsphere formulations with drug, commercial name and technology employed in the preparation
|Patent Number||Drug Used|
Table 2: List of microsphere formulation under approval
|Metformin Hcl||Sodium Alginate||Anti-diabetic|
|Amoxicillin Trihydrate||Ethyl Cellulose||Antibiotic|
|Captopril||Sodium Alginate, Home, Chitosan, Pectin||ACE Inhibitor|
|Ketoprofen||Xanthan Gum, Pectin, Sodium alginate||Analgesics|
|Ketorolac||Eudragit Rs100, Eudragit Rl100||Anti-inflammatory|
|Selegiline||Sodium alginate||MAO-B Inhibitor|
Table 3: List of microsphere formulations approved with polymer and their category
As there is no permanent remedy for Parkinson’s disease, treatment must be continued. The patient if fails to continue the treatment it leads to death. Hence formulation with controlled, sustained release helps the patient to reduce the dosing frequency and enhance the bioavailability of the drug. Microspheres are one of the best formulation choices, suitable for drugs having controlled and sustained release properties.
This review article shows that there is a high scope for developing microsphere formulations using novel technologies and combining various strategies used in cell sorting, gene delivery, targeted, effective drug delivery to small tissues and organs in the body. The main scope of microsphere formulations is they can be modified, released at desired rate and site. These formulations can be used in controlled and sustained release rates of the drugs. Furthermore, it shows enhancing bioavailability and protecting the drug from chemical, enzymatic degradation, and preventing the first-pass metabolism. Therefore, all these mucoadhesive/ buccoadhesive, magnetic and floating microspheres make one of the best choices for developing novel drug delivery systems.
This review was done by affiliation of Department of Pharmacy, Annamalai University, Annamalai Nagar, Chidambaram, Tamil Nadu, and India.
Compliance with Ethical Standards
This article does not contain any studies with human participants or animals conducted by any author.
Conflict of Interest
The authors declared that they have no conflict of interest.
- S. Jeganath, D. Ash, S. Sathesh Kumar, S. Keerthi Nair, Senthil Kumaran, et al. Controlled drug delivery system–A review, research. J Pharm Tech, 11 (2018), 2:797-804.
- Md. Gayoor Khan, Topic–The novel drug delivery system, World J Pharm Pharm Sci, 6 (2017), 477–487.
- M. Bansal, S. Jamil, Micellar microparticles: A novel approach to topical drug delivery System, Int J App Pharm, 10 (2018) 1–5.
- R. Verma, S. Verma, S. Kumar, Microsphere-A Novel drug delivery system. ResChronicle in Hea Sci, 5 (2019), 5-14.
- S. rajput, P. agrawal, A. Pathak et al. A review of microspheres: Methods of preparation and evaluation, World J Pharm Pharm Sci, 1 (2019), 422-438.
- M. Jamini, and S. Rawat, A review of microsphere. Res. J. Pharm. boils. chem. Sci, 4 (2013), 1223–33.
- S. Khan, T. Tiwari, N. Rao, A. Joshi, B. Dubey. Microspheres: A review, World J Pharm Pharm Sci, 1 (2012), 125–145.
- D. Gurunath, M. Hanmant, R. Indrayani et al. A review of microspheres: Types, method of preparation, characterization, and application. AJPTech, 11 (2021) 1–7.
- V. Prasanth, AC. Moy, S. Mathew, R. Mathapan, Microspheres an overview. Int J Res Pharm Biomed Sci, 2 (2011), 8:332
- B. Prasad, V. Gupta , N. Devanna, K. Jayasurya, Microspheres as a drug delivery system – A Review, JGTPS, 5 (2014), 1961−72.
- S. Saini, S. Kumar, M. Choudary, Microspheres as controlled drug delivery system; an updated review. Int. J. Pharm. Sci. Res, 9 (2018), 1760-68.
- D. Gurunath, M. Hanmant, R. Indrayani, A Review on Microspheres: Types, method of preparation, characterization and application, Asian J of Pharm Tech., 11 (2021), 1-7.
- M. Lengyel, N. Kallai-Szabo, V. Antal, A. Jozsef Laki et.al, Micro particles, microspheres, and microcapsules for advanced drug delivery, Sci Pharm, 20 (2019), 87.
- S. Tazib Rahaman, J. Mukherjee, A review of mucoadhesive microspheres as an efficient drug delivery system, Indo Am J Pharm Sci, 10 (2020), 01.
- M. Mohan, H. Sujitha, V. Rao, M. Ashok, B. Arunkumar, A brief review of mucoadhesive microspheres. IJRRPAS, 4 (2014), 975–86.
- A. Kumar, S. Jha, R. Rawal, P. Chauhan, S. Maurya, Mucoadhesive microspheres for novel drug delivery system: A Review, Am J Pharm Tech Res, 3 (2013), 197–213.
- D. Diwakar, A. Krishnan, R. Balakarishnan, V. Ebenezer, “A Review of advanced methods and preparation of mucoadhesive microsphere, Int J Curr Res, 12 (2020), 12053-12056.
- S. Ekama, M. Ilomuanya, C. Azubuike et al, Mucoadhesive microspheres of maraviroc and tenofovir designed for pre-exposure prophylaxis of hiv-1: An in vitro assessment of the effect on vaginal lactic acid bacteria micro flora, hiv/aids-research and palliative care, 13 (2021), 399-413.
- D. Zahn, A. Weidner, K. Saatchi et al. Biodegradable magnetic microspheres for drugtargeting, temperature controlled drug release, and hyperthermia, Curr Dir Biomed Eng, 5 (2019), 161–164.
- R. Shaw, T. Chakraborty, Magnetic microspheres as a novel drug delivery system: A review, Int J Adv Res, 8 (2020), 150–159.
- Kakar, Satinder, Batra, Deepa, Singh, et al. Magnetic microspheres as magical novel drug delivery system: A review, J Acute Dis, 2 (2013), 1–12.
- M. Lengyel, N. Kállai-Szabo, V. Antal et al., Microparticles, microspheres, and microcapsules for advanced drug delivery, Sci Pharm, 87 (2019), 20.
- S. Zhang, G. Li, J. Man, et al., Fabrication of microspheres from high-viscosity bioink using a novel microfluidic-based 3d bioprinting nozzle. Micromachines, 11 (2020), 681.
- A. Birajdar, M. Deshmukh, R. Sheet, A review of gastro-retentive floating microspheres, J drug deliv Ther, 11 (2021), 1:131-138.
- S.P. Mishra, S. nayak, D. Mishra, A. kumar, Gastro retentive mucoadhesive microsphere for the management of gastric infection, J Drug Deliv ther, 9 (2019), 680–686.
- D. Rai, D. Pandey, NP. Jain, SK. Jain, Formulation development and evaluation of floating microsphere of famotidine for the treatment of peptic ulcerm, J Drug Deliv Ther, 9 (2019), 426–431.
- N. Ramalingam, N. Ramesh, V. Govindan et al. Formulation and evaluation of mucoadhesive tablet of pantoprazole sodium, Int J Recent Sci Res, 11 (2020), 39610–39618.
- E. Lagreca, V. Onesto, C. Di Natale et al., Recent advances in the formulation of plga micro particles for controlled drug delivery, Prog Biomater, 9 (2020), 153–174.
- Bolourchian, Bahjat, Design and in vitro evaluation of eudragit-based extended release diltiazem microspheres for once- and twice-daily administration: the effect of coating on drug-release b, Turk J Pharm Sci, 16 (2019), 3:340–347
- Kakar, Satinder, Singh, Ramandeep, Preparation of magnetic microspheres of mesalamine by phase separation emulsion polymerization technique, afr j pharmacy pharmacol, 8 (2014), 246–258.
- S. Bertoni, L. NDolci, B. Albertini, N. Passerini, Spray concealing a versatile technology for advanced drug-delivery systems. Therapeutic Delivery, 9 (2018), 833–845.
- A. Ibrahim, R. Ali. Characterization of microparticles prepared using the solvent evaporation method, use of alcohol-soluble cellulose acetate butyrate as a carrier, J Pharm Pharmacogn Res, 8 (2020), 4:336–345.
- P. Sacco, S. Pedroso-Santana, Y. Kumar et al., Ionotropic gelation of chitosan flat structures and potential applications, Molecules, 26 (2021), 660.
- P. Patil, S. Singh, J. Sarvanan, Preparation and evaluation of microspheres of flurbiprofen. Int J Pharm Sci, 9 (2018), 5388–5393.
- G. Praveen Kumar, S. Mishra, M. Bajpai, Formulation and evaluation of controlled-release of telmisartan microspheres: In vitro/in vivo study, J Food Drug Anal, 22 (2014), 542 - 548.
- H. Yasin, B. Al-Taani, M. Sheikh Salem, Preparation and characterization of ethylcellulose microspheres for sustained-release of pregabalin, Res Pharm Sci, 16 (2021), 1:1.
- W. Wang, Q. Meng, Qi Li, Chitosan derivatives and their application in biomedicine, Int J Mol Sci, 21 (2020), 487.
- A. S. Kulkarni, SS. Bhujbal. Alginate microspheres containing curcumin: preparation, characterization, and in vitro human hemoglobin glycosylation assay, Asian J Pharm Clin Res, 12 (2019), 221–225.
- P. Patil, S. Singh, J.Sarvanan, Preparation and evaluation of microspheres of flurbiprofen. Int J Pharm Sci & Res, 9 (2018), 5388–5393.
- T. Virmani, J. Gupta. Traditional and emerging applications of microspheres: A Review, Int. J. Pharm. Sci, 8 (2017), 3252–3260.
- S. Fanning, Selkoe, D. Dettmer, Parkinson’s disease: Proteinopathy or lipidopathy? npj Parkinson’s Dis, 6 (2020), 3.
- J.P. Harris, J.C Burrell, Struzyna, et al. Emerging regenerative medicine and tissue engineering strategies for Parkinson’s disease, Apj Parkinson’s Dis, 6 (2020), 1-14.
- T. Lee, E. Yankee, A Review of Parkinson’s disease treatment Neuroimmunol Neuroinflammation, 8 (2021).
- Jiang, Ying, Zhang, Xuemei, Mu et al., Preparation and evaluation of injectable Rasagiline mesylate dual-controlled drug delivery system for the treatment of Parkinson’s disease, Drug Delivery, 25 (2018), 143-152.
- V. Kumar, Rasagiline-loaded plga nanoparticles: design and evaluation, Chron Pharm Sci, 1 (2017), 160–173.
- K. Janapareddi, A. Kandhula, Development and ex vivo evaluation of rasagiline mesylate mucoadhesive micro emulsion for intranasal delivery using box-behnken design, IJBPR, 8 (2019), 2514–2522.
- N. Bali, P. Salve, Fabrication and evaluation of selegiline hcl embedded transdermal film for managing parkinson’s disease, J Drug Deliv Ther, 9 (2019), 344-351.
- S. Kumar, J. Ali , S. Baboota, Design expert® supported optimization and predictive analysis of selegiline nanoemulsion via the olfactory region with enhanced behavioural performance, parkinson's disease, 27 (2016), 435101.